6UVK

OXA-48 bound by inhibitor CDD-97

Summary for 6UVK

• Entry DOI: 10.2210/pdb6uvk/pdb
• Descriptor: Beta-lactamase, 1-{4-[4-(2-ethoxyphenyl)piperazin-1-yl]-1,3,5-triazin-2-yl}piperidine-4-carboxylic acid, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: inhibitor, beta-lactamase, oxa-48, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 4
• Total formula weight: 115152.74

Authors

Taylor, D.M.,Hu, L.,Prasad, B.V.V.,Sankaran, B.,Palzkill, T.G. (deposition date: 2019-11-02, release date: 2020-05-06, Last modification date: 2023-11-15)

Primary citation

Taylor, D.M.,Anglin, J.,Park, S.,Ucisik, M.N.,Faver, J.C.,Simmons, N.,Jin, Z.,Palaniappan, M.,Nyshadham, P.,Li, F.,Campbell, J.,Hu, L.,Sankaran, B.,Prasad, B.V.V.,Huang, H.,Matzuk, M.M.,Palzkill, T.
Identifying Oxacillinase-48 Carbapenemase Inhibitors Using DNA-Encoded Chemical Libraries.
Acs Infect Dis., 6:1214-1227, 2020

PubMed Abstract: Bacterial resistance to β-lactam antibiotics is largely mediated by β-lactamases, which catalyze the hydrolysis of these drugs and continue to emerge in response to antibiotic use. β-Lactamases that hydrolyze the last resort carbapenem class of β-lactam antibiotics (carbapenemases) are a growing global health threat. Inhibitors have been developed to prevent β-lactamase-mediated hydrolysis and restore the efficacy of these antibiotics. However, there are few inhibitors available for problematic carbapenemases such as oxacillinase-48 (OXA-48). A DNA-encoded chemical library approach was used to rapidly screen for compounds that bind and potentially inhibit OXA-48. Using this approach, a hit compound, CDD-97, was identified with submicromolar potency ( = 0.53 ± 0.08 μM) against OXA-48. X-ray crystallography showed that CDD-97 binds noncovalently in the active site of OXA-48. Synthesis and testing of derivatives of CDD-97 revealed structure-activity relationships and informed the design of a compound with a 2-fold increase in potency. CDD-97, however, synergizes poorly with β-lactam antibiotics to inhibit the growth of bacteria expressing OXA-48 due to poor accumulation into . Despite the low activity, CDD-97 provides new insights into OXA-48 inhibition and demonstrates the potential of using DNA-encoded chemistry technology to rapidly identify β-lactamase binders and to study β-lactamase inhibition, leading to clinically useful inhibitors.

PubMed: 32182432
DOI: 10.1021/acsinfecdis.0c00015

Experimental method

X-RAY DIFFRACTION (2.2 Å)